Many compounds have been identified as carcinogenic agents, particularly neoplasia and tumor promoters. In the study of the mechanism of neoplasia and tumor promotion, phorbol esters have received particular attention and are characterized as extremely potent tumor promotion agents (Blumberg et al., "Specific Receptors for Phorbol Ester Tumor Promoters and Their Involvement in Biological Responses" (Chapter 5) in Mechanisms of Tumor Promotion (Volume III) (Thomas J. Slaga, ed., CRC Press, Inc., Boca Raton, Fla. 1984)).
Some phorbol compounds, however, have also been disclosed as useful in the inhibition of neoplasia and tumor promotion. The diterpene alcohol phorbol has been disclosed as an antineoplastic agent (U.S. Pat. No. 4,716,179), and the phorbol derivatives phorbol-12,13-diacetate (PDA), phorbol-12,13-dipropionate (PDPr), phorbol-12,13-dibutyrate (PDBu), phorbol-12,13-dibenzoate (PDB), and phorbol 12,13,20-triester (PTA) have been disclosed as inhibiting tumor promotion by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in 7,12-dimethylbenzanthracene (DMBA)-initiated mouse skin (Schmidt et al., "Simple Phorbol Esters as Inhibitors of Tumor Promotion by TPA in Mouse Skin," in Carcinogenesis and Biological Effects of Tumor Promotors, 7, 57-63 (Hecker et al., eds., Raven Press, New York 1982)). The disclosed results regarding the phorbol derivatives, however, have not been replicated, and no inhibition of neoplasia and tumor promotion by TPA by these phorbol derivatives was found in a different mouse strain (Slaga et al., "Studies on the Mechanism of Skin Tumor Promotion: Evidence for Several Stages in Promotion," Proc. Natl. Acad. Sci. USA, 77(6), 3659-3663 (June 1980)). Moreover, the results indicating the inhibition of tumor promotion are inconsistent with the disclosure that PDB and PDBu are tumor promoters (Baird et al., Cancer Res., 31, 1074-1079 (1971); Thielman et al., in Fortschritte der Krebsforschung, 7, 171-179 (Schmidt et al., eds., Schattauer, Stuttgart 1969)) and the general view that the tumor promoting actions of phorbol derivatives are additive and do not cancel each other (Driedger et al., Cancer Res., 40, 339-346 (1980)).
Thus, there remains a need for effective inhibitors of neoplasia and tumor promotion, particularly such inhibitors which do not have adverse side-effects and can be safely applied to mammals, especially humans. The present invention provides such inhibitors of neoplasia and tumor promoters, including the potent tumor promoter of the phorbol ester class TPA, which is also known as phorbol 12-myristate 13-acetate (PMA).
These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.